Abstract 2213: Investigation of treatment resistance with DNA-damage agents in patients with triple negative breast cancer by ctDNA
Authors: Rafael R. Brianese, Giovana T. Torrezan, Marina De Brot, Maria Nirvana Formiga, Vladmir de Lima, Fabiana B. Makdissi, Dirce Maria Carraro
Journal: Cancer Research (2019)

Abstract Loss of function (LOF) germline mutation in BRCA1 increases the risk of breast cancer, especially the triple-negative breast cancer (TNBC) subtype, a very aggressive tumor. TNBC exhibits high variability at both molecular and clinical aspects. BRCA impairment is associated to deficiency in homologous recombination repair (HRD) and tumor with HRD has benefit from treatment with drugs that induces DNA damage and also with PARP inhibitor. We previously detected that a significant fraction of TNBC diagnosed in young Brazilian exhibits BRCA1 impairment by both mechanisms - germline pathogenic mutation and promoter hypermethylation - and that this group of tumor presented better overall survival (Brianese et al 2018). In the current study our aim is to comprehensively characterize the resistance to DNA-damage agents in patients with TNBC associated or not with HRD by investigating somatic mutations in circulating plasma DNA (cDNA). Thus, are also investigating 6 serial cDNA samples of patients during neoadjuvant and adjuvant chemotherapy treatment. Patients are subjected to genetic testing using a 26-gene panel including the homologous recombination (HR) predisposing genes for classifying the TNBC in hereditary or sporadic. The somatic mutations identified in the tumor biopsy by using a gene panel containing frequently mutated genes in breast tumor cancer have been screened in serial plasma samples to check allele frequency of the somatic mutation in circulating DNA and to correlate to therapy response. Results: We have enrolled 32 TNBC patients of which 28 were tested by germline variants. Based on 18 samples we had 50% of pathological complete response. Pathogenic mutations were identified only in BRCA1 in 5 out of 28 (17.8%) patients. Additionally, variants of uncertain significance (VUS) were identified in 18 out of the 26 genes (64.2% - 18/28) patients, being ATM the most affected gene by VUS. In terms of somatic variants, tumor mutation burden (TMB) analysis showed that 25% has high and 75% low TMB, with no association with BRCA1 germline status. Also, we found an average three somatic variants per tumor (range 1-7) and used as tumor marks in the screening of circulating DNA in plasma (cDNA). Somatic mutations in TP53 were identified in all tumor biopsy samples. In cDNA in plasma before treatment, confident detection of at least one tumor mutation was observed in 6 out of 8 patients (75%), including somatic mutations in TP53 and SAMD9 genes. Serial plasma cDNA samples were completely investigated for two patients until now and the results showed great association with the clinical response data suggesting that the chemotherapy-resistance mechanisms can be investigated by ctDNA in TNBC. Supported by FAPESP, CNPq and Capes. Citation Format: Rafael R. Brianese, Giovana T. Torrezan, Marina De Brot, Maria Nirvana Formiga, Vladmir de Lima, Fabiana B. Makdissi, Dirce Maria Carraro. Investigation of treatment resistance with DNA-damage agents in patients with triple negative breast cancer by ctDNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2213.